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WO1988009664A1 - Systemes de liberation par erosion et diffusion utilisant une matrice de polyphosphazene - Google Patents

Systemes de liberation par erosion et diffusion utilisant une matrice de polyphosphazene Download PDF

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Publication number
WO1988009664A1
WO1988009664A1 PCT/US1988/001965 US8801965W WO8809664A1 WO 1988009664 A1 WO1988009664 A1 WO 1988009664A1 US 8801965 W US8801965 W US 8801965W WO 8809664 A1 WO8809664 A1 WO 8809664A1
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WO
WIPO (PCT)
Prior art keywords
polymer
polyphosphazene
active substance
bioerodible
release
Prior art date
Application number
PCT/US1988/001965
Other languages
English (en)
Inventor
Cato T. Laurencin
Robert S. Langer
Harry R. Allcock
Thomas X. Neenan
Original Assignee
Massachusetts Institute Of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Massachusetts Institute Of Technology filed Critical Massachusetts Institute Of Technology
Publication of WO1988009664A1 publication Critical patent/WO1988009664A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers

Definitions

  • the invention relates to polyphosphazene sustained and controlled release systems.
  • Polyphosphazenes are polymers with backbones consisting of nitrogen and phosphorous separated by alternating single and double bonds. Each phosphorous atom generally is covalently bonded to two side chains ("R").
  • the repeat unit in polyphosphazenes has the general structure (1):
  • bioerodible drug delivery systems consisting of a polyphosphazene polymer covalently bonded to a therapeutic agent, i.e., the drug is part of the class of systems called "pendant side chain” systems in which the drug is covalently attached to the polymer backbone.
  • one aspect of the invention features an inorganic polymeric matrix system (as distinguished from pendant side chain systems) for delivering a biologically active substance to an aqueous environment.
  • the system includes a polyphosphazene polymer matrix body which physically entraps the biologically active substance to be released. Physically entrapped, as used herein, means that, until the body is introduced into the aqueous environment, the substance is physically retained within, but not covalently bonded to, the polyphosphazene polymer.
  • the system components are designed and selected so that, when the system is exposed to an aqueous environment, the active substance is released to the environment at a sustained and controlled rate over a prolonged period.
  • sustained release we mean release over a period substantially longer than the period of biological activity achieved by administration in a single dose.
  • controlled release we mean release at rates that are predictable over time.
  • the biologically active substance is a therapeutic agent
  • the polymeric body provides controlled, sustained in vivo release of the therapeutic agent to a physiological fluid of a living organism (e.g. a mammal).
  • the polymer is a bioerodible polyaminophosphazene that has side chains (e.g., imidizole groups or amino acid esters) that are capable of hydrolyzing when exposed to a physiological environment.
  • bioerodible means a polymer that dissolves or degrades within a period that is acceptable in the desired application , (usually in vivo therapy), e.g. less than about five years and most preferably less than about one year, once exposed to an aqueous environment, e.g., a physiological solution of pH6-8 having a temperature of between about ' 25°C and 45°C.
  • the active molecule is released from the polymer substantially by diffusion when the system is exposed to an aqueous environment. Release by diffusion means release resulting from mechanisms other than erosion. A polymer is considered to release "substantially by diffusion” if its average release rate is no more than twice the rate achieved with a comparable non-eroding polymer. 5
  • a second aspect of the invention features reinforcing vivo tissue by applying a bioerodible polyphosphazene to the tissue. The polymer is selected to erode as its structural support is no longer needed.
  • a third aspect of the invention features 10 treating a living organism to provide controlled sustained release of ammonia and phosphate at a desired location by implanting a bioerodible inorganic polymer body comprising a polyphosphazene at the location.
  • the polyphosphazene release system is IS particularly advantageous because it has an inorganic backbone that is biocompatible overtime and (in the bioerodible embodiments) that degrades to harmless small-molecule products: ammonia, phosphate and water.
  • the system can be made bioerodible to avoid surgical 20. Removal of the polymer after use, and the bioerosion products are relatively benign in low concentrations.
  • the system can accomodate a large variety of drugs including small drugs and macromolecules.
  • Figs, la and b are graphs depicting polymer 30.. degradation over time.
  • Figs. 2-6 are graphs depicting release of various molecules over tissue. II. Structure
  • the preferred delivery system includes a bioerodible polyaminophosphazene polymer having side chains that hydrolyze in a physiological environment. 5
  • the hydrolysis results in the chemical breakdown and eventual erosion of the polymer.
  • Mixed throughout and entrapped by the the polymer is a therapeutic agent that is released at a controlled and sustained rate when the system is placed in a physiological environment.
  • the preferred polyphosphazenes are those in which at least a portion (generally greater than 10% of the side chains (the R groups in formula 1) are capable of hydrolyzing in a physiological environment. Hydrolysis of the side chain results in hydrolysis of
  • hydrolyzing side chains are unsubstituted and substituted imidizoles and a ino acid esters in which the group is bonded to the phosphorous atom through an amino linkage (polyphosphazene polymers in
  • polyaminophosphazenes 20. which both R groups are attached in this manner are known as polyaminophosphazenes).
  • polyimidizolephosphazenes some of the "R" groups on the polyphosphazene backbone are imidizole rings, attached to phosphorous in the backbone through a ring nitrogen
  • R can be organic residues that do not participate in hydrolysis, such as methyl phenoxy groups or other groups shown in Allcock et a. ⁇ . (1977) Macromolecule 10:824-830.
  • 3Q hydrolyzing can be any alkyl, aralkyl, or aryl group having 20 carbon atoms or less (more preferably 12 carbon atoms or less); or a heteroalkyl, heteroaralkyl, or heteroaryl group having 20 or less carbons and heteroatoms (more preferably 12 or less carbon or heteroato s) .
  • the groups can be bonded to the phosphorous atom through e.g., an oxygen, sulfur, nitrogen, or carbon atom.
  • the preferred polyphosphazenes are made by reacting poly(dichlorophosphazene) with the appropriate side chain nucleophiles, which displace the chlorines. Desired proportions of hydrolyzible to nonhydrolyzible side chains in the polymer can be achieved by adjusting 10 . the quantity of the corresponding nucleophiles that are reacted with the poly(dichlorophosphazene) .
  • the preferred polyphosphazenes have a molecular weight of over 100,000. If the molecular weight is below 100,000, the polymer may lose some of its film 15 forming capability.
  • therapeutic agent means any agent used to treat or prevent any disease or disorder of the body. Both low molecular weight (less than about 1000) agents and higher molecular weight 2o (greater than about 1000) agents (macromolecules) can be used in the delivery system. Representative agents include hormones (and hormone fragments and analogues), e.g., testosterone, progesterone, luteinizing hormone-releasing hormone (LHRH); diuretics, e.g., 25 .
  • chlorothiazide e.g., morphine
  • antibiotics e.g., tetracycline
  • antipsychotic drugs e.g., anticancer drugs, e.g., methotrexate, actinomycin D, vinblastine, and cytosine arabinoside
  • vaccines e.g., ibuprofen and flurbiprofen.
  • antiarthritic drugs e.g., ibuprofen and flurbiprofen.
  • the system can be shaped and sized for buccal, oral, vaginal, intrauterine, ocular, and anal insertion; for skin patches, e.g., to fit behind the ear; or for parenteral insertion or injection, e.g., throguh a syringe (in which case the delivery systems would be in the form of powder in which each particle is small enough to fit through a syringe tip) .
  • the bioerodible characteristic of the polymer is particularly important where the mode of administration of the delivery system is parenteral insertion or injection, as the fact that the polymer eventually dissipates makes it unnecessary to go into the body parenterally to remove the system once it is depleted of the agent.
  • the preferred delivery systems can contain up to 50% by weight (more preferably up to 30% by weight) of therapeutic agent. If too low a proportion of polymer is present, the mechanical properties of the delivery system may be adversly affected.
  • the therapeutic agent is physically entrapped by the polymer, preferably by casting a polymer/agent mixture.
  • sustained release means that the agent is released continuously from the system over an appropriate prolonged period of time.
  • the period of time over which the agent is released can be adjusted for a particular system by varying the size of the system and by varying the type side chains on the polyphosphazene.
  • Controlled release means that the agent is released from the system within a desired dosage range for most of the sustained period.
  • the amount of agent released may begin to decrease due to a depletion of the supply of agent.
  • the sustained period (2-5 days), it is common to see a initial burst of agent released that is somewhat higher than the long-term release rate.
  • the agent can be released from the delivery system by one or both of two general mechanisms. (1) The agent can be released as the polyphosphazene erodes; and (2) the agent can be released by diffusion of the • agent and aqueous fluid through the polymer and into the environment of use.
  • the mechanism by which the agent is released from the system can be selected by adjusting the proportion of hydrolyzable to non-hydrolyzible side chains on the polyphosphazene.
  • the matrix is implanted in a location accessible only by surgery, it is desirable to use an erodible matrix.
  • Tetrahydrofuran THF (MCB Omnisolve) was distilled under nitrogen from sodium benzophenone ketyl . All other solvents used were reagent grade or better.
  • p-Methylphenol (Aldrich) was sublimed before use.
  • Imidazole (Aldrich) was recrystallized from absolute alcohol. Sodium spheres (Aldrich) were used as received.
  • H N R spectra were recorded on a Bruker 5 WP-200 spectrometer operating at 200MHz in the Fourier transform mode. All data are for samples in C g D g .
  • p NMR spectra were recorded on a Varian CFT-20 spectrometer operating at 32 MHz in the Fourier transform mode. All spectra were recorded for samples
  • Hexachlorocyclotriphosphazene (Ethyl 25 Corporation) was purified by two recrystallizations from hexane and by two sublimations at 50°C (6.7 Pa: 0.05 torr) .
  • Poly(dichlorophosphazene) was prepared by the thermal polymerization of (NPCl-)- at 250°C. An average of 50%-60% conversion to the linear polymer was 30. obtained.
  • the sodium salt of p-methoxypheno1 was prepared as follows. A 500 ml, 3 neck round bottomed flask containing a magnetic stir bar was equipped with a gas inlet, a water cooled condenser and an addition funnel. The flask was flame dried and allowed to cool while being flushed with a stream of nitrogen. The flask was flame dried and allowed to cool while being flushed with 5 a stream of dry nitrogen. The flask was charged with 300 ml freshly distilled THF follwed by the addition of NaH (4.12g, 60% NaH in mineral oil). The flask was cooled by means of an ice bath and to the slurry was added dropwise through the addition funnel a solution of
  • the polymer was 0 redissolved in the minimum amount of dry THF and the precipitation procedure was repeated three times.
  • This polymer was prepared using the same methods and materials as with the copolymler above, with the exception that 8 grams (.069 moles) of [NPC1 2 ]
  • H-progesterone New England Nuclear
  • progesterone Sigma
  • Polymeric slabs were placed in 20 ml scintillation vials (Kimble) with 10 ml of buffer. Percent degradation was determined by freeze drying samples at specific time intervals and measuring weight loss. Since the rate of degradation of the 20% imidazole substituted polyphosphazene was low, and extinction coefficient for the first 10% of polymer degradation was formulated and percent degradation with time was determined spectrophotometrically, and confirmed by freeze drying samples periodically in a parallel study. The degradation of 45% imidazole substituted polphosphazene was performed in deionized water at pH 5.5. All degradation studies were performed in quadruplicate.
  • Fig. l shows erosion profiles for both 20% and 45% imidazole containing polyphosphazenes.
  • Degradation of 20% imidazole substituted polyphosphazene was quite slow, with 4% of polymer degrading in 600 hours (Fig. la) . This low rate of degradation would be expected since degradation is imidazole dependent.
  • 30% of the 45% imidazole substituted polyphosphazene degraded in approximately 300 hours (Fig. lb), with a marked decrease in degradation rate after that point. With kinetics continuing at the decreased rate the polymer would be expected to have a degradative lifetime of 3 years.
  • Polyphosphazenes synthesized containing 80% imidazole and 20% methoxyphenoxy degraded on the order of hours in room humidity. Such variation in degradative characteristics provides the ability to formulate release systems based primarily on diffusion, erosion, or a mixture of erosion and diffusion.
  • rats were sacrificed by C0 2 asphyxiation, and the polymer disk was removed.
  • the disk was dissolved in THF, and progesterone present was determined as stated below.
  • the collected buffer sam ⁇ les were read spectrophotometrically at a wavelength of 380 nm, the absorption maximum for p-nitroaniline. At this wavelength, neither the polymer nor its degradation products have been found to absorb. (The extinction 5 coefficient for p-nitroaniline dissolved in the buffer used was 97.1 ml/mg-cm. ) Absorbance measurments were made using a Perkin Elmer 553 U.V./Vis. Spectrophoto ⁇ meter.
  • Polypeptide release was demonstrated using 2.5% loaded BSA. Release from these matrices consisted of a burst of almost 25% percent followed by release over 1000 hours ⁇ in which a total of 55% of protein was released (Fig. 6). In an attempt to remove the burst, 2.5% loaded BSA matrices were dipped in 20% solutions of 20% imidazole polyphosphazene in THF for 3 seconds. Referring to Fig. 6, the polymer coating step eliminates the burst effect, with 5% release occurring during the first 4 hours. At 1000 hours 45% of the protein is released.
  • polyphosphazenes that are not biodegradable can be used in the delivery system; in such systems, the therapeutic agent is released via diffusion exclusively.
  • nonbiodegradable polyphosphazenes are described by Allcock et al., J. Inorg. Chem. ⁇ 1:515 (1982).
  • the system can be used to release biologically active substances to aqueous fluids other than physiological fluids in animals.
  • pesticides and poisons can be released slowly to an infested site such as an agriculture site.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une substance biologiquement active, par exemple un agent thérapeutique, est administrée à partir d'un système polymère inorganique comprenant un corps polymère de polyphosphazène, la substance active étant emprisonnée physiquement par le corps polymère. Lorsque le système est exposé à un fluide aqueux, par exemple lorsqu'il est implanté dans un fluide physiologique d'un mammifère vivant, l'agent est libéré du corps polymère à une vitesse ou cadence soutenue et régulée.
PCT/US1988/001965 1987-06-10 1988-06-09 Systemes de liberation par erosion et diffusion utilisant une matrice de polyphosphazene WO1988009664A1 (fr)

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US6077087A 1987-06-10 1987-06-10
US060,770 1987-06-10

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0467389A2 (fr) * 1990-07-19 1992-01-22 University Of Kentucky Research Foundation Système de délivrance de drogue à l'aide de l'interaction entre une protéine ou polypeptide et un polymère biodégradable hydrophobe
WO1992005778A1 (fr) * 1990-10-05 1992-04-16 Massachusetts Institute Of Technology Microcapsules polymeres reticulees de maniere ionique
US7265199B2 (en) 2000-04-11 2007-09-04 Celonova Biosciences Germany Gmbh Poly-tri-fluoro-ethoxypolyphosphazene coverings and films
EP1874729A1 (fr) * 2005-04-15 2008-01-09 Parallel Solutions, Inc. Polyphosphazenes biodegradables contenant des groupes pyrrolidone lateraux
US7922764B2 (en) 2006-10-10 2011-04-12 Celonova Bioscience, Inc. Bioprosthetic heart valve with polyphosphazene
US9080146B2 (en) 2001-01-11 2015-07-14 Celonova Biosciences, Inc. Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface
US9107850B2 (en) 2004-10-25 2015-08-18 Celonova Biosciences, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same
US9114162B2 (en) 2004-10-25 2015-08-25 Celonova Biosciences, Inc. Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US10973770B2 (en) 2004-10-25 2021-04-13 Varian Medical Systems, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993071A (en) * 1971-09-09 1976-11-23 Alza Corporation Bioerodible ocular device
US4440921A (en) * 1982-06-21 1984-04-03 Research Corporation Coupling of polyorganophosphazenes to carboxylic acid
US4495174A (en) * 1982-06-21 1985-01-22 Research Corporation Anesthetic polyorganophosphazenes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993071A (en) * 1971-09-09 1976-11-23 Alza Corporation Bioerodible ocular device
US4440921A (en) * 1982-06-21 1984-04-03 Research Corporation Coupling of polyorganophosphazenes to carboxylic acid
US4495174A (en) * 1982-06-21 1985-01-22 Research Corporation Anesthetic polyorganophosphazenes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 102, Entry 32116L, (DEVISSER et al.), January 1984. *
DISSERTATION ABSTRACTS, No. DA8409012 (AUSTIN), December 1983. See entire document. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0467389A2 (fr) * 1990-07-19 1992-01-22 University Of Kentucky Research Foundation Système de délivrance de drogue à l'aide de l'interaction entre une protéine ou polypeptide et un polymère biodégradable hydrophobe
EP0467389A3 (fr) * 1990-07-19 1994-02-02 Univ Kentucky Res Found
US6306406B1 (en) 1990-07-19 2001-10-23 University Of Kentucky Research Foundation Drug delivery system involving interaction between protein or polypeptide and hydrophobic biodegradable polymer
WO1992005778A1 (fr) * 1990-10-05 1992-04-16 Massachusetts Institute Of Technology Microcapsules polymeres reticulees de maniere ionique
US7265199B2 (en) 2000-04-11 2007-09-04 Celonova Biosciences Germany Gmbh Poly-tri-fluoro-ethoxypolyphosphazene coverings and films
US9080146B2 (en) 2001-01-11 2015-07-14 Celonova Biosciences, Inc. Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface
US9107850B2 (en) 2004-10-25 2015-08-18 Celonova Biosciences, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same
US9114162B2 (en) 2004-10-25 2015-08-25 Celonova Biosciences, Inc. Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US9597419B2 (en) 2004-10-25 2017-03-21 Boston Scientific Limited Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US10973770B2 (en) 2004-10-25 2021-04-13 Varian Medical Systems, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same
JP2008536978A (ja) * 2005-04-15 2008-09-11 パラレル ソリューションズ，インク． ピロリドン側基を含む生分解性ポリホスファゼン
EP1874729A4 (fr) * 2005-04-15 2010-08-25 Parallel Solutions Inc Polyphosphazenes biodegradables contenant des groupes pyrrolidone lateraux
EP1874729A1 (fr) * 2005-04-15 2008-01-09 Parallel Solutions, Inc. Polyphosphazenes biodegradables contenant des groupes pyrrolidone lateraux
US7922764B2 (en) 2006-10-10 2011-04-12 Celonova Bioscience, Inc. Bioprosthetic heart valve with polyphosphazene

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